ABSTRACT Infertility and spontaneous abortion (SAB) are significant public health problems, each affecting up to 20% of reproductive-aged couples in the United States. As couples increasingly postpone childbearing to the later reproductive years, many seek infertility treatment, which has relatively low success rates, costs an estimated $5 billion per year, and is associated with adverse pregnancy outcomes. Therefore, identifying modifiable risk factors for subfertility and SAB is an important public health goal. The potential effects of air pollution on risk of subfertility and SAB are understudied. The few existing human studies have major limitations including retrospective study design, small study size, suboptimal assessment of exposure and outcome, inadequate control for potential confounding variables, and limited generalizability. The proposed study will assess the relation of several air pollutants to risk of subfertility and SAB in two interrelated preconception prospective cohort studies in North America and Denmark. Using web-based recruitment, data collection, and follow-up, we have enrolled over 16,500 women attempting pregnancy, collectively comprising the largest preconception cohort study ever conducted on factors related to fertility and SAB. We have collected prospective data on time-to- pregnancy, SAB, potential confounders in both partners, and residential addresses at baseline and on bi-monthly follow-up questionnaires for all participants, providing the foundation for accurate time-varying assessment of exposure to air pollution throughout the preconception and early pregnancy periods. Our specific aims are to develop spatio-temporal models of ambient PM2.5, NO2, and O3 for the etiologic time periods of interest, construct measures of traffic and roadway density around each residence using geographic information system software, and assign appropriate time-varying estimates of exposure. Among 18,500 women, we will examine the association between individual measures of air pollution (PM2.5, NO2, O3 and measures of traffic density) and fecundability, the cycle-specific probability of conception. We will evaluate the same measures of air pollution with risk of SAB. We will also utilize state-of-the-art statistical methods, including predictive k-means clustering, to examine the effects of pollutant mixtures, with an emphasis on speciation of PM components. Strengths of this application include its large study size, preconception enrollment of a geographically and ethnically diverse cohort of pregnancy planners, assessment of repeated measures of exposure during the preconception and early pregnancy periods, excellent control for individual-level and neighborhood-level confounding via collection of data on a wide range of covariates, and the use of multi-pollutant modeling techniques. The present application is cost-effective in leveraging already-established cohort studies funded by the NICHD. The proposed study addresses novel and important reproductive health outcomes that have had only limited study in relation to air pollution. Study results are likely to inform primary prevention of infertility and SAB, and add to evidence used by regulators to improve air quality.